Hypoxic and hepatic coma are common and important causes of morbidity and mortality in the United States: this proposal outlines studies related to the pathogenesis of, and potential new rational treatment strategies for these disorders. Studies of hepatic coma will seek to quantify the diffusion and transport of neurotoxic short-chain fatty acids (SCFA) as they enter the brain from the blood. Other studies will identify the organs that are primarily concerned with SCFA homeostasis, as they are potential target organs for theraputic interventions. We will attempt to stimulate ammonia detoxification by skeletal muscle, an important organ in ammonia homeostasis, by infusing amino acids that have been shown to increase glutamine synthesis in rat muscle. This should have the effect of lowering blood ammonia levels and improving hepatic coma due to hyperammonemia. The protection from hyperammonemic coma afforded by methionine sulfoximine will be investigated by means of a mathematical modeling approach that will describe potential changes in the compartmentation of cerebral ammonia metabolism. Finally, we will extend observations that indicate that the infusion of glycolytic intermediates increases the oxidation state of cytochrome a,a3 by making quantitative measurements of the cerebral metabolic rate for oxygen. This effect is probably mediated by increase in red cell 2,3-diphosphoglycerate and a shift to the right of the oxygen-hemoglobin dissociation curve. An increase in the oxygen delivery to the brain due to a pharmacologic manipulation of hemoglobin would represent a potential major advance in the therapy of hypoxic and ischemic brain disease. These studies will use the cyclotron-produced positron-emitting isotopes 11C, 13N, and 15O to label metabolites and toxins. These isotopes are well suited to in vivo, non-invasive studies of cerebral metabolism in humans, and can be used to construct positron emission tomographs of the brain given the appropriate imaging equipment.